Cellular oxygen sensors and other 2-oxoglutarate-dependent enzymes as novel treatment targets for diseases - Peppi Karppinen
Oxygen sensing is central to metazoan biology and has implications for human disease. 2-oxoglutarate-dependent dioxygenases (2OGDDs) are an enzyme family of >60 members in human that share the same reaction mechanism requiring O2, Fe2+ and 2-oxoglutarate (2OG). Their affinity for O2 varies. Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases (HIF-P4Hs) are 2OGDDs that function as key cellular O2 sensors. Other 2OGDDs include P4H-TM, the fourth HIF-P4H mutated in a neurological HIDEA syndrome, numerous histone lysine demethylases (KDMs) of which some also sense oxygen and the fatty acid hydroxylase PHYH, mutated in Refsum disease, and its isoform PHYHD1 that are relatively understudied.
2OGDDs can be targeted with small molecule compounds, such as the HIF-P4H inhibitors of which the first has been accepted for the treatment of renal anemia. We hypothesize that such inhibitors can in addition to anemia be used to treat ischemic, metabolic and inflammatory conditions. We also anticipate that other 2OGDDs can be targeted with small molecule inhibitors to for example to treat cancer. Our objective is here to investigate 2OGDDs as treatment targets for cardio-metabolic and neurodegenerative diseases and hepatocellular cancer.
Koivunen P & Kietzmann T (2018) Hypoxia-Inducible Factor Prolyl 4-Hydroxylases and Metabolism. Trends Mol Med 24: 1021-1035.
Chakraborty AA, Koivunen P & Kaelin WG,Jr (2019) Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 363: 1217-1222.
Rahikkala E, Koivunen P & Uusimaa J (2019) Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome). Genet Med 21: 2355-2363.
Rahtu-Korpela L & Koivunen P (2014) HIF prolyl 4-hydroxylase-2 inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction. Diabetes 63: 3324-3333.
Rahtu-Korpela L & Koivunen P (2016) Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis. Arterioscler Thromb Vasc Biol 36: 608-617.